Pharmacokinetics Flashcards
(109 cards)
1
Q
What will make any pharmacological therapy fail clinical trails?
A
The drug is unable to reach its target organ(s)
At concentrations sufficient to have a therapeutic effect
2
Q
Does a successful drug need to be able to cross the same physiologic barriers that exist in the body to limit access to foreign substances?
A
Yes
3
Q
What is pharmacokinetics?
A
It is essentially what the body does with the drug
A drug enters the body, circulates within the body, is changed by the body, and leaves the body
4
Q
What are the 4 major steps of drug movement in the body?
A
Absorption
Distribution
Metabolism (biotransformation)
Excretion (elimination)
5
Q
What is drug absorption?
A
Drug absorption can occur by a number of mechanisms designed to either exploit or breach the body’s physiologic barriers
Method of drug administration greatly affects its absorption
6
Q
What is drug distribution?
A
Following absorption, the drug will utilize the body’s distribution systems such as blood and lymphatic vessels to reach its target in an appropriate concentration
7
Q
What processes limit the drug to be able to access its target?
A
Drug metabolism
Drug excretion
8
Q
What is drug metabolism?
A
The body inactivates the drug through enzyme degradation especially in the liver
9
Q
What is drug excretion?
A
After being metabolized, the drug is excreted out of the body
Primarily through the kidneys (urine), liver (bile), and gut (feces)
10
Q
Will only a fraction of the drugs that successfully bind to the target receptor site exert its pharmacological effect?
A
Yes
11
Q
Does metabolism of a drug in the body produce both active and inactive metabolites (drug products after metabolism)?
A
Yes
Active metabolites can exert a pharmacological effect either on the drug target receptor or other receptors
12
Q
What is drug absorption a prerequisite for?
A
Establishing optimal plasma drug levels for therapeutic drug actions
13
Q
Do drugs have to cross the cell membrane?
A
Yes
14
Q
What drugs can easily diffuse through the cell membrane?
A
Nonpolar molecules (steroids)
Most drugs and polar molecules are larger and, therefore, simple diffusion through the layers of the cell membrane is not an option
15
Q
What factors affect a drug’s ability to cross a bilayer membrane?
A
Lipid solubility (the more lipid soluble the drug, the easier it will cross)
Degree of ionization (charge) (charged molecules cannot cross (must use pores/channels) and hydrophobic drug molecules can generally pass through easily)
Molecular size (small-sized molecules can cross the cell membrane easily)
Shape of the drug molecule (molecules that can contort to fit through the cell membrane can cross more easily)
16
Q
What is the blood brain barrier?
A
An extremely selective barrier that separates the circulating blood from the brain extracellular fluid in the CNS
Formed by capillary endothelial cells connected by tight junctions
17
Q
What is necessary to create the blood brain barrier?
A
Astrocytes (CNS supporting cells)
18
Q
What is allowed through the blood brain barrier?
A
Water, some gases, and lipid soluble molecules by passive diffusion
19
Q
Does the blood brain barrier allow selective transport of molecules?
A
Yes, such as glucose and amino acids that are crucial to neural function
20
Q
What can the blood brain barrier prevent?
A
The entry of potential neurotoxins by way of an active transport (requires energy) mechanism
21
Q
Does the BBB prevent passive diffusion of most drugs from systemic to cerebral circulation?
A
Yes
Drugs that are designed to act on the CNS must be either sufficiently hydrophobic to easily pass biological membranes or use existing facilitative/active transport systems
22
Q
How can drugs that act on the CNS be administered?
A
Through intrathecal infusion (injected directly into the CSF, anywhere along the spine)
The intrathecal route is useful for single or limited doses and to treat meningitis or CNS cancers
It is impractical for drugs that need to be taken on a more regular/daily basis
23
Q
What is the blood labyrinth barrier?
A
A homeostatic mechanism that protects the inner ear
24
Q
What is essential for the function of the blood labyrinth barrier?
A
Maintenance of a constant composition of the inner ear fluids
25
Can small molecular weight molecules enter the perilymph in a dose and time dependent manner?
Yes
26
Can several ototoxic drugs and bacteria cross the BLB and enter the perilymph?
Yes
27
Is the rate of elimination from the perilymph much slower than that from serum?
Yes
28
What can a disruption of the BLB cause?
Disturbances of inner ear homeostasis, resulting in functional disruption of the auditory system
29
What is the blood-placental barrier?
It serves as a barrier between maternal and fetal circulation and protects the fetus from noxious agents
Antigens and antibodies can cross both ways
30
Can small molecules cross the placental barrier?
Yes
Many viruses, including cytomegalovirus (CMV), rubella (German measles), varicella-zoster (chicken pox), measles, HIV (AIDS), Zika, and poliovirus can cross the placenta
31
Do bacteria and other protozoa ordinarily cross the BPB?
No, but there are some exceptions
32
Is the BPB a strong barrier for drugs?
No
Most can cross easily
Non-ionized and lipid-soluble drugs cross most easily
33
What are some factors besides physiological barriers that can affect the rate of drug movement across cell membranes?
Solubility of the drug - drugs dissolved in solutions are more rapidly absorbed than insoluble drugs
Route of drug administration - the closer the site of administration is to a blood vessel, the faster the drug can be absorbed
34
What is the enteral route of administration?
Placed directly into the GI tract
Oral or rectal administration
35
What is the topical route of administration?
Drugs applied to the surface of body and includes
Transdermal administration
Otic
Nasal
Ophthalmic
36
What is the parenteral route?
Drugs administered through routes other than enteric or topical
Drug bypasses the GI tract and its barriers
Inhalation
Intradermal (administered in the dermis) and subcutaneous (administered under the dermis)
Intravenous
intrarterial
Intramuscular
intraosseous
Sublingual (enters venous circulation)
Intrathecal (injected into the spinal canal/subarachnoid space)
Intraperitoneal (injected in the peritoneum)
37
Is the enteral route the simplest route of administration?
Yes
38
What are some benefits of the enteral drug route?
Ease of self administration; no skilled medical care needed
Very portable
Less likely to introduce systemic infections unlike parenteral route
39
Does the enteral route expose the drug to harsh environments?
Yes
Lipid soluble drugs pass through the GI tract most easily
Food in the stomach may or may not alter the rate of absorption
pH of the stomach and drug may interfere with drug absorption
Presence of other drugs in the stomach may cause a drug interaction (in the oral route)
Drugs go through a first-pass metabolism in the liver
40
What is the first-pass metabolism in the liver?
Drugs that are administered orally pass from the GI tract to the portal veins and enter the liver before entering the systemic circulation
This system protects individuals from the effect of ingested toxins, which are detoxified in the liver
Any drug that exhibits first-pass metabolism must have appropriate dosage to ensure effective concentration on target organs because of some inactivation in the liver
Checkpoint
41
Are non-enteral routes of administration subject to the first-pass metabolism by the liver?
No
42
What are some advantages of parenteral drug administration?
An intravenous (IV) administered drug is immediately available in the circulation
An intramuscular (IM) or subcutaneous (SC) administration has a slower entry into the circulation than I/V but faster than enteral administration
Fast onset of drug action
The amount of drug reaching the system will be the same for all routes of parental administration (non-intravenous routes will take longer to reach peak values in circulation)
Route for drugs not absorbed by the gut or too irritant for the gut
IV administration allows for more controlled delivery
One injection can have lasting effects
IV route can deliver continuous medication
43
What are some disadvantages of the parenteral drug route?
Greater risk of addiction with drugs that are injected as the onset of action is very rapid
Not practical for patients who cannot self administer injections
Belonephobia (fear of needles and injections) limits this route
High risk for hepatitis, HIV, etc., if needles are shared
Most dangerous route of administration (bypasses all the body's natural defenses)
Potentially fatal air bubbles (IV) can be introduced
Strict asepsis is required
Requires training and cost is generally higher
44
What are some advantages to subcutaneous routes?
Slow onset, may be used to administer oil-based drugs
45
What are some disadvantages of subcutaneous routes?
Slow onset, small volumes
46
What are some advantages of intramuscular routes?
Intermediate onset, may be used to administer oil-based drugs
47
What are some disadvantages of intramuscular route?
Can affect lab tests (creatine kinase), intramuscular hemorrhage, painful
48
What are some advantages of an intravenous route?
Rapid onset, controlled drug delivery
49
What are some disadvantages to intravenous route?
Peak-related drug toxicity
50
What are some advantages to intrathecal route?
Bypasses BBB
51
What are some disadvantages to intrathecal route?
Infection, highly skilled personnel required
52
What is bioavailability?
Subcategory of drug absorption
Bioavailability = quantity of drug reaching systemic circulation/quantity of drug administered
53
What is the bioavailability of IV drugs?
1 (maximum)
Injected directly into the systemic circulation
54
What is the bioavailability of orally administered drugs?
< 1
Dose would have to be increased to reach the same amount of drug received via the IV route
55
What is bioavailability dependent on?
Route of administration
Chemical form of the drug
Patient factors such as GI enzymes and pH, and hepatic metabolism
56
How are drugs soluble in aqueous solutions administered?
Orally
57
How are oil soluble dugs administered?
Subcutaneously or IM
58
Is bioavailability especially important with generic drugs?
Yes
These drug have the same molecule structure, but concentration and route of administration may differ
FDA mandates that generics must have 90% of the bioavailability of the parent compound
59
How are drugs distributed after absorption?
By the circulatory system (blood plasma) and to a minor degree by the lymphatic system
60
Why is the concentration of drugs in plasma often used to determine therapeutic drug levels?
Because the amount of drug actually taken up by the target organs is difficult to measure
Often correlated well with the effect of the drug on its target site
61
What affects drug concentration in the plasma?
Distribution of the drug in various tissues and compartments as well as blood flow variability between different organs (liver and kidney usually receive the most blood flow)
62
What are the two forms that drugs will take in blood?
Bound to plasma proteins (most commonly albumin)
Free or unbound drug (active part of the drug)
63
Within each compartment of the body, is the drug split between bound and free forms (blood)?
Yes
Plasma protein binding reduces the drug’s availability for diffusion (transport) to its target site
Only the free drug form can pass across gaps between capillary cells to leave plasma and enter interstitial fluids
As free drug leaves the plasma, the bound drug becomes “unbound”
64
What is the ratio of bound:unbound drugs in the blood?
They stay the same in the body
As drugs become bound, others become unbound
65
Do unbound drugs actually bring about the action?
Yes
66
What are characteristics of bound drugs?
No effect
Remains in the compartment (vasculature) longer
A drug that exhibits high level of protein binding requires a higher concentration
67
What are the characteristics of the unbound form of a drug?
Exerts desired effect on target drug receptor sites in the target organ(s)
68
What is drug metabolism/drug biotransformation?
Convert lipid soluble drugs to water soluble metabolites so that the drugs can be more easily excreted by the kidneys
The liver contains the greatest quantity and diversity of metabolic enzymes
The majority of drug metabolism occurs in the liver
Drug metabolism also occurs in kidneys, lungs, nerves, skin, plasma, and CI tract
69
What are biotransformation reactions classified as?
Oxidation/Reduction or Phase I
Conjugation/Hydrolysis or Phase II reactions
70
What is oxidation/reduction or phase I?
Phase 1 reactions modify the chemical structure of a drug through oxidation/reduction
The liver has enzymes that facilitate these reactions
Some drugs are administered in an inactive prodrug form so that they can be metabolically altered in the liver to the activated form (not active until metabolism)
The most common pathway in the liver is the cytochrome P450 system (CYP pronounced “sip” enzymes) that mediates oxidative reactions
71
What is the purpose of the prodrug strategy?
Facilitates oral bioavailability
Decrease GI toxicity
Prolong the elimination half life of the drug
72
Does an individual's complement of cytochrome P450 (CYP) enzymes in the liver determine the rate and extent to which individuals can metabolize various drugs?
Yes
More CYP enzymes, the faster the drug will break down
73
What happens if the cytochrome P450 enzymes are induced?
It would increase the rate of metabolism
Increasing the rate of metabolism would decrease the action of the drug
74
What happens if the cytochrome P450 enzymes are inhibited?
It would decrease the rate of metabolism
Decreasing the rate of metabolism would increase the action of the drug
75
What does conjugation/hydrolysis work?
Hydrolyze or conjugate a drug to a larger polar molecule by adding other molecular groups such as glutathione, sulfate, and acetate
This reaction inactivates the drug or enhances the drug solubility and excretion rate into urine or bile
76
What is conjugation?
Forming a compound by joining two or more chemical compounds
77
What is hydrolysis?
A reaction involving the breaking of a bond in a molecule using water
78
What are the effects of phase I and II reactions dependent on?
The presence of other drugs taken by the patient at the same time
79
What are barbiturates?
Powerful inducers of enzymes (mediate phase I reactions)
Can speed up the metabolic process and decrease the action of drugs being taken concomitantly
80
Can other drugs inhibit enzymes?
Yes
Slowing down the metabolic process and increasing the action of drugs being taken concomitantly
81
What are the outcomes of phase I and phase II reactions?
Convert an active drug to inactive (most common outcome, the inactive drug is formed from the active parent drug)
Convert an inactive drug form (prodrug) to active (inactive parent drug is converted to active drug after metabolism)
Convert an active drug to active (an active parent drug is converted to a second active drug)
82
What is drug excretion?
It is the movement of a drug and/or its metabolites out of the body
Primarily through renal excretion (urine)
Also through biliary excretion (feces)
Minor amounts through respiratory (breath – i.e., alcohol, useful for Breathalyzer), and dermal routes (sweat)
Even smaller amounts through breast milk during lactation
83
How much is renal flow comprised of total systemic blood flow?
25%
The kidneys are, therefore, continually exposed to drugs in the bloodstream
84
What happens to a drug that is fat soluble that reaches the kidneys?
It will be reabsorbed by the kidneys and placed back into the bloodstream
85
What will happen if kidney function is affected?
Excretion of the drug will take longer and can increase drug toxicity
86
What affects kidney function?
Age (kidney function declines with age)
Drug toxicity
Altered kidney function from disease such as diabetes (impaired renal blood supply), hypertension, renal disease such as polycystic kidneys and glomerulonephritis, and cancers
87
What is drug clearance?
The rate of elimination of a drug from the body relative to the concentration of the drug in the plasma or the rate at which the drug would need to be cleared from the plasma to account for the change sought by the drug in the body
Clearance = Metabolism + Excretion ÷ Drug(plasma)
Metabolism and excretion are expressed as rates (amount ÷ time)
88
What are metabolism and excretion referred to as?
Clearance mechanisms
89
Although metabolism and excretion are different physiologic processes, is the endpoint equivalent?
Yes
Reduction in circulating levels of an active drug
Clearance(total) = Clearance(renal) + Clearance(hepatic) + Clearance(other)
90
What is zero-order elimination kinetics?
Elimination of a constant quantity per time unit of the drug quantity present in the organism
Rather rare, mostly occurring when the elimination system is saturated
Salicylates (aspirin), ethanol (alcohol), cisplatin
91
What is first order elimination kinetics?
Elimination of a constant fraction per time unit of the drug quantity present in the organism
The elimination is proportional to the drug concentration
95% of drugs are eliminated in this fashion
92
Is the half-life constant for most drugs?
Yes
93
What is half life?
The time required for the serum drug concentration to decrease by 50%
When the half-life of a drug is short, it is removed quickly from the body, i.e., short duration of action
When the half-life is long, the drug is removed slowly from the body, i.e., long duration of action
94
How long (in half-life) does it take for a drug to clear from the body?
4 to 5 half-lives
95
How does renal failure affect half-life?
It decreases excretion rates and increases the half-life of drugs
96
How long does it take for a drug to build up to a steady state?
4 to 5 half-lives
97
What does knowledge of a drugs half-life allow us to do?
Estimate frequency of dosing of the drug required to maintain the therapeutic range of the drug in plasma
98
What is the formula that can be used to calculate the elimination half-life of a drug?
Based on volume of distribution and clearance of drug
t1/2 = 0.693 x Vd ÷ Clearance
99
Do factors that affect the volume of distribution and clearance of a drug also effect the half-life of a drug?
Yes
100
What effects volume distribution of drug?
Aging (decreased muscle mass leads to decreased distribution)
Obesity (increased adipose mass leads to increased distribution)
Pathologic fluid (increased distribution)
101
What effects clearance of drugs?
Cytochrome P450 induction (increased metabolism) - increased clearance
Cytochrome P450 inhibition (decreased metabolism) - decreased clearance
Cardiac failure - decreased clearance
Hepatic failure - decreased clearance
Renal failure - decreased clearance
102
What is redistribution of drugs?
Redistribution is the movement of drugs from specific site of action to nonspecific sites of action
Redistribution to a nonspecific site will terminate the drugs action
103
Does a highly absorbed drug generally require a lower dose than poorly absorbed drugs?
Yes
104
Does a highly distributed drug require higher drug doses?
Yes
105
Does the elimination rate determine the frequency of drug doses to maintain therapeutic levels?
Yes
Liver and kidney function (involved in clearance) affect the half-life and, therefore, drug dosage
106
What does therapeutic dosing seek to maintain?
The peak (highest) plasma concentration below toxic levels
And the trough (lowest) plasma concentration above minimally effective levels
107
What is a loading dose?
Higher initial or loading dose of drugs administered to compensate for drug distribution in the tissues from plasma
108
What is a maintenance dose?
Once steady state is reached, subsequent drug doses must replace only what is lost through metabolism and excretion
109
Can drugs change from first order to zero order kinetics?
Yes
For some drugs the body’s capacity to eliminate drugs through hepatic metabolism becomes saturated at therapeutic or slightly above therapeutic values
This is when it switches over
Elimination rate does not increase with increasing concentration
Continuous drug administration in such cases, can result in rapid drug accumulation with drug concentrations reaching toxic values
